The Pathogenesis of pp65-Induced Anti-dsDNA Antibody in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex, heterogeneous system autoimmune disease involving a wide array of organ damage. Genetic, hormonal, and environmental factors contribute to the full development of the disease. The exact underlying molecular mechanisms of SLE remain to be fully elucidated albeit extensively studied. The association of Human cytomegalovirus (HCMV) infection with systemic lupus erythematosus (SLE) has been discussed widely over the past decade. HCMV phosphoprotein 65 (pp65) has been demonstrated to be a possible immunogen that act as an accelerator inducing autoantibody and flare up of lupus nephritis in SLE pathogenesis. The pp65336-439 showed higher positivity rate in the serum of SLE patients. In BALB/c mice, the pp65336-439 infusion could drive the tolerance break and induce a variety of antibodies to cellular components, including chromatin and dsDNA. Interestingly, the higher serum anti-dsDNA antibody level accompanied with severe immune complex deposition on kidney and the binding of antibody to dsDNA is competed by pp65422-439. The role of pp65336-439 in triggering the SLE onset remains to be elucidated. To meet this goal, we extend the previous experiences in rheumatologic studies to explore the antigenicity of SLE-specific B cell epitope derived from pp65336-439 and the pathogenic role of antibody to dsDNA induced by pp65336-439 in lupus nephritis. Here we aimed at elucidating the precise mechanisms of anti-pp65336-439 antibody cross-reactive to dsDNA or other cellular proteins. We intend to determine the pathogenesis of pp65422-439-induced autoantibody in SLE and clarify the cytokine profile changes in the BALB/c and NZBW/F1 mice post-immunized with pp65422-439. Hopefully, the combination of these harvesting results in animal studies and clinical association studies can provide a reliable marker for medical diagnosis. The specific aims as follows: 1. To localize the SLE-specific B cell epitope in pp65336-439 and verify the relationship among anti-candidate pp65 peptide antibody, clinical phenotypes especially lupus nephritis 2. To determine whether the candidate pp65 peptide could trigger the lupus nephritis. 3. To identify mice renal proteins targeted by anti-dsDNA antibody 4. Fine mapping of SLE-specific B epitope in pp65336-439. 5. To investigate the associations of pp65 peptide immunity with cytokine profile, IFN signature genes (Toll-like receptor and Interferon regulatory factors etc.) and clinical phenotypes in BALB/c and NZBWF1 mice as well as Taiwanese SLE patients.

Project ID:PC10501-1597
External Project ID:MOST103-2314-B182-067-MY3